THE TAT PROTEIN OF HIV-1 INDUCES TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION - IMPLICATIONS FOR HIV-1-ASSOCIATED NEUROLOGICAL DISEASES

Human immunodeficiency virus (HIV) infection may cause a dementing ill ness. HIV-mediated dementia is clinically and pathologically correlate d with the infiltration of activated macrophages and elevated levels o f tumor necrosis factor (TNF)-alpha, both of which occur in an environ ment of small numbers of infected cells. We examined the possibility t hat HIV protein Tat, which is released extracellularly from infected c ells, may induce the production of TNF-alpha. Tat induced TNF-alpha mR NA and protein production dose-dependently, primarily in macrophages b ut also in astrocytic cells. The TNF-alpha induction was NF-kappa B-de pendent and could be eliminated by inhibiting protein kinase A or prot ein tyrosine kinase activity. In addition, Tat-induced TNF-alpha relea se was also linked to phospholipase C activation. However, Tat effects were independent of protein kinase C. These observations suggest that Tat may provide an important link between HIV and macrophage/glial ce ll activation and suggest new therapeutic approaches for HIV dementia.